Virtual Screening Strategies in Drug Design

Rodrigues, Rossana Lott; Mantoani, Susimaire P.; Almeida, Jonathan Resende de; Pinsetta, Flávio Roberto; Semighini, Evandro P.; Silva, Vinicius B. da; Silva, Carlos Henrique T. P. da

doi:10.5935/1984-6835.20120055

Cited by 28 publications

(22 citation statements)

References 164 publications

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“…Thus, the techniques that use the 3D structure of the macromolecular target are complementary strategies to studies that are based on previous knowledge of ligands to allow the assessment of the modes of interaction of potential compounds, that are selected for the pharmacophore model in the active site, respecting the limitations of the molecular volume for docking. 17 The combination of pharmacophore models with docking has been widely exploited in drug design. 52 Typically, the techniques that have a lower computational demand, as pharmacophore model, are initially applied, and the filtered molecules are consecutively directed to other strategies such as docking.…”

Section: Docking-based Virtual Screeningmentioning

confidence: 99%

“…molecular docking) can help identify compounds with chemical, electronic and steric properties that are essential for biological activity. 17 Due to chemical and structural diversity, the natural products have been widely recognized as an important source of new hit/lead through virtual screening. 18 This study aimed to prioritize promising molecules derived from natural products for the T. cruzi FPPS (TcFPPS) inhibition assays by pharmacophore models and docking approaches.…”

Section: Introductionmentioning

confidence: 99%

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Virtual Screening for the Selection of New Candidates to Trypanosoma cruzi Farnesyl Pyrophosphate Synthase Inhibitors

Oliveira¹,

Araújo²,

Júnior³

et al. 2018

J. Braz. Chem. Soc.

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Chagas disease is a tropical parasitic disease that is caused by Trypanosoma cruzi and causes 12,000 deaths per year, mainly in Latin America. The available drugs for treating have severe limitations, including poor efficacy and high toxicity. One way to overcome these limitations is targeting priority molecules with computational tools to direct in vitro assays against validated targets. Farnesyl pyrophosphate synthase (E.C. 2.5.1.10) is an enzyme that participates in the initial stage of sterol biosynthesis, and its inhibition causes damage to membrane integrity, leading to parasite death. With the aim to identify potential inhibitors against this target from T. cruzi, hierarchical virtual screening approaches were performed through a combination of ligand-based pharmacophore models and molecular docking. First, pharmacophore model filtering resulted in 15,154 molecules that had the minimum structural requirements for inhibition (QFIT > 0). These molecules were subsequently submitted to molecular docking routine, which resulted in 11,762 molecules (Grid Score between-232.74 to-0.96 kcal mol-1). The top 30 ranked molecules in these approaches were grouped in self-organizing maps. These analyses showed four promising compounds from natural products that mimic the major interactions present in the substrate/ inhibitor, which indicates that these molecules can be assayed by in vitro experiments.

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Section: Docking-based Virtual Screeningmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Virtual Screening for the Selection of New Candidates to Trypanosoma cruzi Farnesyl Pyrophosphate Synthase Inhibitors

Oliveira¹,

Araújo²,

Júnior³

et al. 2018

J. Braz. Chem. Soc.

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“…13 Entretanto, a identificação de uma nova espécie química obtida de um produto natural não garante a sua atividade em sistemas biológicos, porém o seu arcabouço molecular pode ser útil na identificação do farmacóforo, ou seja, o conjunto das características eletrônicas e estéricas responsáveis pelo efeito biológico. 13,14 O reconhecimento dessas características farmacofóricas é importante para racionalizar a busca por fármacos, uma vez que, identificada a estrutura do composto protótipo, esta poderá ser modificada com o intuito de melhorar suas propriedades farmacodinâmicas e farmacocinéticas. 14,15 A busca por novas espécies químicas obtidas de produtos naturais é muito importante dada a sua diversidade e complexidade estrutural.…”

Section: Produtos Naturais E O Planejamento De Fármacosunclassified

“…13,14 O reconhecimento dessas características farmacofóricas é importante para racionalizar a busca por fármacos, uma vez que, identificada a estrutura do composto protótipo, esta poderá ser modificada com o intuito de melhorar suas propriedades farmacodinâmicas e farmacocinéticas. 14,15 A busca por novas espécies químicas obtidas de produtos naturais é muito importante dada a sua diversidade e complexidade estrutural. 13 Embora tenham ocorrido grandes avanços nas técnicas de obtenção e purificação de substâncias naturais, há ainda, uma grande dificuldade para sua síntese.…”

Section: Produtos Naturais E O Planejamento De Fármacosunclassified

Virtual Screening applied to search of inhibitors of Trypanosoma cruzi Trypanothione Reductase employing the Natural Products Database from Bahia state (NatProDB)

Paixão¹,

Pita²

2016

Rev. Virtual Quim.

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Neglected Tropical Diseases (NTDs) affect primarily the most vulnerable populations in developing countries and are the major causes of bacterial, parasitic and viral infections. According to the World Health Organization (WHO), Chagas disease, caused by Trypanosoma cruzi, affects 21 countries in Latin America and it is a public health problem. There is no effective treatment for this disease, especially in its chronic phase, since there is a low perspective of financial return to the pharmaceutical industry. Thus, one way to work around this limitation is through the Virtual Screening based on the structure of Trypanothione Reductase of Trypanosoma cruzi (TcTR) using the AutoDock v.4.2 program, we selected the best compounds listed from the Natural Products Database of Bahia State (NatProDB), classifying them according to their energy values of protein-ligand interactions (-12,41 kcal/mol a -8,59 kcal/mol). Our analysis also revealed, through automatic analysis of docking conformations using a self-organizing map (AuPosSOM), which innovative chemical groups are present in NatProDB and which could assist in the drug design against NTD. The use of these computational techniques can help us to verify which interactions are required to inhibit selectively this enzyme, a validated target, and that could eventually result in novel antiChagas disease age ts.Keywords: Chagas disease; Trypanothione Reductase; Virtual Screening; NatProDB, AuPosSOM. ResumoAs Doenças Tropicais Negligenciadas (DTN) afetam principalmente as populações mais vulneráveis dos países em desenvolvimento e estão entre as maiores causas de infecções bacterianas, parasitárias e virais. Segundo a Organização Mundial de Saúde (OMS), a doença de Chagas, causada pelo Trypanosoma cruzi, afeta 21 países da América Latina, sendo considerada um problema de saúde pública. Ainda não há tratamento efetivo para esta doença, principalmente na sua fase crônica, uma vez que não há perspectiva de retorno financeiro à indústria farmacêutica. Uma forma de contornar esta limitação é através da Triagem Virtual baseada na estrutura da Tripanotiona Redutase de Trypanosoma cruzi (TcTR), utilizando o programa AutoDock v.4.2. A partir deste programa, selecionamos compostos com os valores de energia de interação proteína-ligante (-12,41 kcal/mol a -8,59 kcal/mol) oriundos da Base de Dados de Produtos Naturais do Semiárido Baiano (NatProDB). Adicionalmente, identificamos através da análise automática das conformações de acoplamento, usando um mapa de autoorganização (AuPosSOM), quais grupos químicos inovadores estão presentes nas moléculas do NatProDB e quais são as interações intermoleculares que podem auxiliar no planejamento de fármacos contra a doença de Chagas. O emprego destas técnicas computacionais podem auxiliar na verificação das interações necessárias para inibir seletivamente esta enzima, um alvo validado no parasito, e que poderão futuramente resultar em novos fármacos anti-chagásicos.

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“…The virtual screening (VS) is a well‐established drug discovery strategy consisting of searching for molecules in silico, that is, through computer simulation of a database of small chemical molecule collections predicted to be biologically active . An important application of this methodology is provided to pharmaceutical industry valuable starting points for medicinal chemistry in the research and synthesis of new drugs.…”

Section: Introductionmentioning

confidence: 99%

Combining electronic properties and virtual screening for the development of new antioxidants: Trolox‐like compounds as application example

Só

Silva

Carvalho

et al. 2020

Int J of Quantum Chemistry

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Oxidative stress is an imbalance between the production of free radicals and the antioxidant defenses of the organism. Heart diseases, anemia, inflammation, and neurodegenerative disorders have been associated with this biological condition. Trolox is a notable antioxidant drug similar to vitamin E, and it is used to decrease the oxidative stress or repair the damage caused by it. In this work, the virtual screening technique is applied to identify compounds with antioxidant activities similar to Trolox.The antioxidant activity of these compounds was assessments by the mechanisms of hydrogen atom transfer and single electron transfer. Properties such as bond dissociation enthalpy, adiabatic ionization potential, Gibbs free reaction energy, spin density, highest occupied molecular orbital (HOMO), and GAP (HOMO-LUMO) energies, obtained from the DFT approach, point out to the predominance of the HAT mechanism for the antioxidant action of these compounds. The obtained results contribute to a better understanding of the chemical and physical properties responsible for antioxidant activity and the design of new antioxidant agents. K E Y W O R D Santioxidant activity, DFT method, oxidative stress, trolox, virtual screening

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Virtual Screening Strategies in Drug Design

Cited by 28 publications

References 164 publications

Virtual Screening for the Selection of New Candidates to Trypanosoma cruzi Farnesyl Pyrophosphate Synthase Inhibitors

Virtual Screening for the Selection of New Candidates to Trypanosoma cruzi Farnesyl Pyrophosphate Synthase Inhibitors

Virtual Screening applied to search of inhibitors of Trypanosoma cruzi Trypanothione Reductase employing the Natural Products Database from Bahia state (NatProDB)

Combining electronic properties and virtual screening for the development of new antioxidants: Trolox‐like compounds as application example

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